CERTAIN 1,2,3,5,6,12,13a-OCTAHYDRO-12-OXO-{8 3,2,1-d,e{9 PYRIDO-{8 1,5{9 -NAPHTHYRIDINES

ABSTRACT

The invention relates to new indole derivatives which are useful therapeutical agents. Said new derivatives are 1,2,3,5,6,12,13,13a-octahydro-12-oxo(3,2,1-d,e)-indolo-(3,2,1-i,j)-pyrido -(1,5)-naphthyridines having the general formula   IN WHICH R1 and R2, which may be the same or different, are selected from H, OH and OCH3, and R3 is selected from H, Cl, Br and -COCO2C2H5.

Unite States Patent [191 Thai et al.

[4 1 Aug. 28, 1973 CERTAIN l,2,3,5,6,12,13A-OCTAHYDRO-l2-OXO- [3,2,l-D,E]PYRlDO-[l,5]-

NAPHTHYRIDINES [75] Inventors: Claude Thal, Malakoff; Pierre Potier, Bois D A rcy; Henri Philippe Husson, Chevreuse, all of France [73] Assignee: Anvar-Agence Nationale de Valorisation de la Recherche, Paris, France 22 Filed: Mar. 17, 1971 21 App]. No.: 125,029

[30] Foreign Application Priority Data Mar. 26, 1970 France 7010846 [52] US. Cl..... 260/293.53, 260/295 A, 260/295 B, 424/267 [51] Int. Cl C07d 29/22 [58] Field of Search 260/295 A, 293.53

[56] References Cited OTHER PUBLICATIONS Bartlett et al., J. Am. Chem. Soc., Vol. 82, pages 5941- 5946, (1960) QDI A 5 Trutneva et al., Chem. Abstracts, Vol. 65, 6l23a-e, Aug. 1966.

Primary ExaminerAlan L. Rotman Attorney-Holman & Stern [5 7] ABSTRACT The invention relates to new indole derivatives which are useful therapeutical agents.

Said new derivatives are l,2,3,5,6,l2,l3,l3a-octahydro-l2-oxo-[3,2,l-d.e]- indolo-[ 3,2, l -i,j]-pyrido-[ 1,5 l-naphthyridines having the general formula in which R and R which may be the same or different, are selected from H, OH and OCH and R is selected from H, Cl, Br and COCO C H 3 Claims, 2 Drawing Figures PATENTEDMIBZ IBH 3 755 335 sum 1 or 2 PATENTEMcza ms sum a nr 2 CERTAIN l ,2,3 ,5,6, l 2, l 3A-OCTAHYDRO- l 2-OXO-[ 3,2, l D,E]PYRlDO-[ 1,5 ]-NAPHTHYRIDINES This invention is concerned with new indole derivatives and their non-toxic acid addition salts with pharmaceutically acceptable acids, a process for their prep aration and a therapeutic composition containing same.

The new indole derivatives according to the invention are l ,2,3,5,6,12,13,13a-octahydro-l2-oxo-[3,2,1- d,e]-indolo-[ 3,2, l ,-i,j]-pyrido-[ l ,5 ]-naphthyridines having the following general formula:

m Lil/ \x N 12 Li 0: 13 \1) Re (I) in which R and R which may be the same or different, are selected from H, OH and OCH and R is selected from H, Cl, Br and COCO C H The invention encompasses all the enantiomers of derivatives of formula (I) and their acid addition salts with pharmaceutically acceptable acids.

The new derivatives according to the invention possess vaso-regulator properties, particularly at the cerebral level, which make them useful therapeutical agents.

The process for the preparation of derivatives of formula (I) according to the invention comprises hydrogenating an indole-derived pyridinium salt having the following general formula:

in which R and R have the above-defined meanings, to give a compound of the formula:

which is optionally oxalylated to give the corresponding. derivative of formula (I) in which R, is CO- cO C H this last derivative being optionally brominated or chlorinated to give the corresponding derivative of formula (I) in which R is Br or Cl.

According to an advantageous embodiment of the process according to the present invention, the indolederived pyridinium salt is hydrogenated under a hydrogen atmosphere and in the presence of platinum, within methanol containing dissolved hydrogen chloride gas.

The invention relates also to a therapeutic composition having in particular a vaso-regulator activity and useful for the treatment of circulatory disorders, particularly at the cerebral level, comprising a derivative of formula (I) or a pharmaceutically acceptable salt thereof, together with a therapeutically administrable vehicle.

Other features of the invention will be apparent from the following detailed description.

In the accompanying drawing, given solely for illustrative purposes:

FIG. 1 represents the IR. absorption spectrum (absorption as a function of wavelength) of one of the compounds according to the invention; and

FIG. 2 illustrates some of the physiological activities of this same compound.

The new indole derivatives according to the invention exhibit the following general formula:

in which R and R which may be the same or different, are selected from H,OH and OCH and R is selected from H,Cl,Br and COCO C H Said derivatives are produced by hydrogenation of an indole-derived pyridinium salt having the following general formula:

Rr- I R 1 in which substituents R and R have the above-defined meanings, the hydrogenation being carried out typically under a hydrogen atmosphere at ordinary temperature and pressure and in the presence of platinum as catalyst, after dissolution of the salt in methanol containing dissolved hydrogen chloride gas, the hydrogenation being followed, if desired, by an oxalylation and the resulting derivative being, in turn, optionally brominated or chlorinated to give the corresponding derivatives of formula (I).

The result of the hydrogenation reaction, i.e., the cyclization, is entirely unexpected.

Indeed, from the constitution of the pyridinium salt, it might have been predicted that hydrogenation would result in complete saturation of the pyridine ring to pentahydropyridine or piperidine without any cyclization.

The hydrogenation reaction is advantageously carried out at ordinary temperature and pressure, with stirring under a hydrogen atmosphere.

The reaction medium, i.e., methanol containing dissolved hydrogen chloride gas, is produced either by dissolving hydrogen chloride gas in pure methanol, or by admixing a given amount of hydrogen chloride gassaturated methanol with pure methanol.

The pyridinium salt concentration of the methanol medium is generally 1 20 percent, and preferably 8- 12 percent, by weight.

Purification of the hydrogenation reaction product is advantageously effected by chromatography.

The oxalylation of the resulting product, to give the corresponding derivative in which R -COCO C H is carried out according to the usual techniques, by means of ethyl oxalate, within ethanol, for example.

This gives the corresponding oxalylated derivative which, on treatment with N-chlorosuccinimide or N- bromosuccinimide within pyridine leads to the chlorinated or brominated derivatives at l3-position, respectively.

To prepare the starting pyridinium salt, the following procedure may be used.

In a first stage, tryptophol is treated with phosphorus bromide, according to the process of HOSl-llNO and Sl-llMODAlRA, Ann., 520, 19 (1953), which gives the following reaction scheme:

E? l. (if

III N (III) scheme:

lOgCHB gives the desired pyridinium salt which is washed with anhydrous ether and is then recrystallized from methanol-ether.

To prepare a pyridinium salt in which substituents R, and R, are other than hydrogen, a tryptophol including such substituents is used as starting material.

To prepare the acid addition salts of compounds of formula (I) with physiologically acceptable acids, the usual techniques are used. Useful acids include, for example, hydrochloric, tartaric, maleic, succinic acids, and the like.

It should be mentioned also that the hydrogenation process according to the invention, when applied to a pyridinium salt unsubstituted with -Cl-l CO Cl-l in the pyridine nucleus, leads also to a cyclization.

The practice of this invention is further illustrated by means of the following examples which are not intended to be limitations on the scope of the invention.

EXAMPLE 1 Preparation of (i)-l,2,3,5,6,12,13,13-a-octahydrol2-oxo-[3,2,l-d,e]-indolo-[3,2,l-i,j]pyrido-[1,5]- naphthyridine (named, hereinafter, Product A) of the formula:

- (VII) To prepare the corresponding pyridinium salt used as starting material to be submitted to hydrogenation, a mixture of methyl homonicotinate (3.5 g) and tryptophyl bromide (2.6 g) is reacted at C, during 45 hours, under a nitrogen atmosphere, the resulting solid material is washed with anhydrous ether and is then recrystallized from ethanol-ether. The melting point of the pyridinium salt is 166 C.

10 g of the resulting pyridinium salt are then dissolved in absolute methanol (250 ml) including an amount of hydrogen chloride gas-saturated methanol within a range from 20 to 80 percent. This solution is stirred at ambient temperature and pressure, under a hydrogen atmosphere, during twenty hours, in the presence of platinum as catalyst, after which the catalyst is filtered oh and the solvent is removed in vacuo. The residue is taken up into water (500 ml), after which, if desired, the solution is filtered and made alkaline with sodium carbonate and then repeatedly extracted with chloroform. A heterogeneous oily crude product which is chromatographically purified over neutral alumina, using benzene or benzene/cyclohexane as eluent, is isolated in a yield of approximately 50 percent.

There is obtained 7 percent of the desired product, with respect to the starting salt, said product having the following physical characteristics:

M.P. 146 C (acetone-hexane) LR. spectrum (Nujol) illustrated in FIG! of the accompanying drawing: peaks at 5.92, 6.10 p. (the reference peaks 6.24 and 9.72 are indicated in this figure).

U.V. spectrum (alcohol): 1r 243 nm logxy: 4.25); 266 (3.97); 294 (3.59); 302 (3.59);

Analysis c n N Calculated in 76.66 6.81 10.52 Found a 76.45 6.65 l0.70

Mass spectrum M 266 Elution with benzene-chloroform makes it possible to isolate, in an amount of about 15 percent with respect to the starting salt, another indole derivative which is a new chemical compound having the formula:

CO CHz mp l70 C.

The other characteristics of this product are:

IR. spectrum (CHCI 1,735, 3,472 cm Mass spectrum M 298 Resolution of aforementioned racemic product A waS carried out using, as active acid, dextrorotatory diparatoluyltartaric acid [11],, +l45 (Cl-lCl as follows:

For resolution purposes, 1 g of racemic base is converted to the salt form with 1.4 g of di-p-toluyltartaric acid in 120 ml of methanol. The reaction mixture is allowed to crystallize.

Isolation of the enantiomers: By successive crystallizations, (+)-l ,2,3,5,6,1 2,1 3 ,1 3a-octahydro-l 2-oxo- [3,2,1-d,e]-indolo-[3,2,l-i,j]-pyrido-[1,5]- naphthyridine, [04],, 150 (CHCl is isolated.

The antipode (-)-l,2,3,5,6,l2,l3,13a-octahydro-l2- oxo-[3,2,1-d,e]-indolo-[3,2,l-i,j]-pyrido-[1,5]- naphthyridine, [011 =l55 (CI-ICI is isolated from the mother-liquors.

EXAMPLE 2 Preparation of the oxalyl derivative of Product A of Example I, having the formula:

OgCgHi (VIII) tives of formula (I).

I Toxicity The investigations carried out on the toxicity of Product A made it possible to determine that the LD thereof, by the intravenous route, in mice, is about 90 mg/kg.

II Action on cerebral circulation This action was evidenced by using successively the method involving the determination of the cerebral rate of flow in dog and the method involving rheoencephalographic investigation.

a. Determination of the cerebral rate of flow in dog.

The method used was disclosed in ANNALES de IUNIVERSITE et de I'A.R.E.R.S., 1969, T.7, p.

120-124, by M.DUPONT, H. EYRAUD, O. ALBERT and MC. LEVY-APPERT-COLLIN.

According to this method, which was also the subject of a communication before the second meeting of AS- SOCIATION des PHARMACOLOGISTES at CLER- MONT-FERRAND, France, 1969, under press for publication in Journal de Pharmacologie, the following data are recorded simultaneously, in particular:

the variations of the rate of flow of the a.vertebralis (principal blood supply to the brain) determined by means of an eleotro-magnetic sensor,

the venous pressure of the internal maxillary vein (reflecting changes in the cerebral circulation).

It is found that at a dosage of 10 mg/kg by the intravenous route (I.V.) Product A increases the cerebral rate of flow in a substantial, durable (thirty minutes) and reproducible manner. Curve I illustrated in FIG.2 of the accompanying drawing shows the variation of the rate of flow, in percent, as a function of time expressed in minutes.

b. Rheoencephalographic investigation By this method are analyzed the variations of electrical impedance related to variations of the blood rate of flow; in this particular case, this method makes it possible to analyze the arterio-venous capillary circulation.

To effect this investigation, the teachings of DAR- DENNE and co-workers, Revue Medicale de Toulouse, 1969, pages 63-82, were taken into account.

This method makes it possible to find that at a dosage of2 and 5 mg/kg by the intravenous route in dog, a substantial and highly durable (sixty minutes) decrease of the cerebral capillary resistance is noted.

Ill Action on peripheral vasomotivity The femoral rate of flow is measured in dog by means of electromagnetic sensors.

At the dosage of 2,5 and 5 mg/kg by the I.V. route, a substantial and durable (15-20 minutes) increase of the rate of flow may be noted, an increase which is apparent from FIG.2 (curve II).

IV Action on respiration The respiratory movements are examined by impedance pneumography in dog. At dosages of 5 and 10 mg/kg, there is stimulation with durable acceleration of the rhythm.

V Action on arterial pressure In dog, at a dosage of 10 mg/kg by the I.V. route, there is noted a rapid transient hypotension folloved by a varying hypertensive stage.

VI Spasmolytic, sympatholytic and ganglioplegic actions on isolated organs a. on rat ileum Product A has a contracturant effect at a dosage of 025-50 'y/ml, and a relaxant effect at a dosage of I00 'ylml,

it has an antagonistic effect on the action of BaCl,, acetylcholine, serotonine at dosages of 25-50 'y/ml; b. on the seminal vesicle of rats: at a dosage of 50 'y/ml, it has an antagonistic effect on the action of adrenalin;

c. on guinea-pig ileum at a dosage of 0.5 -y/ml is has a contracturant effect,

at a dosage of -y/ml is has a relaxant effect, it has an antagonistic efi'ect on the action of nicotine at 5 7/ ml,

it has an antagonistic effect on the action of histamine at 25 ylml.

It is apparent from the above tests that Product A possesses spasmolytic, antiserotonine, sympatholytic, ganglioplegic and antihistaminic effects at markedly contracturant dosages.

The high therapeutical usefulness of Product A is apparent from the following Table in which the various aforementioned activities of Product A are compared with the corresponding activities of two known prod- 10 ucts of same type, i.e., ebumamonine and vincamine.

Thus, the derivatives of the invention may be used as drugs for the treatment of circulatory disorders, particularly at the cerebral level.

The therapeutic composition according to the invention may be administered by the oral, parenteral or rectal route, in unit dosage form, each unit dose containing 1-20 mg, and preferably -10 mg of active ingredient. The daily dosage regimen will generally be of the order of 23 unit doses.

Examples of pharmaceutical forms of the composition according to the invention are given hereinafter: Oral route: tablets containing each 5 mg active material Product A 1.000 kg Lactose 1 ,000 kg Maize starch 2.400 kg Talc 0.400 kg Magnesium stearate 0.200 kg Mix Product A with the lactose and starch. Wet and granulate. Dry at 45 C. Sieve. Add the tale and magnesium stearate.

Daily dosage regimen: 2 to 5 tablets daily lnjeetable route: lnjectable solution, 10 mg active material per unit close Product A, hydrochloride 0.5 g Water for injectable preparation, to make I00 ml Dissolve. Filter through sterilizing MILLIPORE filter. Distribute into 2 ml ampoules. Sterilize in an autoclave at 105 C, during one-half hour.

Daily dosage regimen: l ampoule daily, by the 1M. or l.V. route Rectal routezSuppositories containing each 20 mg active material Product A 2 g Semisynthetic glycerides 1 kg Mix Product A with a small amount of melted excipient at 50 C. Combine this mixture with the remaining amount of melted excipient. Cast into suitable moulds, to obtain suppositories weighing 1 g each, which are then cooled.

Daily dosage regimen: l suppository daily.

We claim:

1. A compound selected from the group consisting of indole derivatives having the formula:

.JW W

in which R; is selected from the group consisting of H and -COCO,C H and their acid addition salts with non-toxic therapeutically acceptable acids.

2. (i)-1,2,3,5,6,l2,l3a-octahydro-l 2-oxo-13- ethoxalyl-[3,2,l-d,e]-indolo-[3,2, l -i,j]-pyrido-[ 1,5}- naphthyridine, having the formula:

CO CzH5 3. (i)-1,2,3,5,6,l2,l3,13a-octahydro-l2-oxo-{3,2,ld,e]-indolo-[3,2,1-i,j]-pyrido-[ 1 ,5]-naphthyridine, having the formula:

and its dextrorotatory and laevorotatory enantiomers. i i t 

2. ( + or - )-1,2,3,5,6,12,13a-octahydro-12-oxo-13-ethoxalyl-(3, 2,1-d,e)-indolo-(3,2,1-i,j)-pyrido-(1,5)-naphthyridine, having the formula:
 3. ( + or - )-1,2,3,5,6,12,13,13a-octahydro-12-oxo-(3,2,1-d,e)-indolo-(3,2,1-i,j)-pyrido-(1,5)-naphthyridine, having the formUla: 